NLRP3 inflammasome activation in aged macrophages is diminished during Streptococcus pneumoniae infection

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 314; no. 3; pp. L372 - L387
• Main Authors: Cho, Soo Jung, Rooney, Kristen, Choi, Augustine M K, Stout-Delgado, Heather W
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2018
• Subjects: Aged; Aging; Animal models; Animals; Cell activation; Cells; Cells, Cultured; Endoplasmic reticulum; Female; Host-Pathogen Interactions; Humans; Immune clearance; Immune response; Immune system; Immunity, Innate - immunology; Infections; Inflammasomes; Inflammasomes - immunology; Innate immunity; Macrophages; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Morbidity; Mortality; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Older people; Pneumococcal Infections - immunology; Pneumococcal Infections - metabolism; Pneumococcal Infections - microbiology; Pneumonia; Pneumonitis; Pretreatment; Protein folding; Proteins; Reducing agents; Rodents; Signal Transduction; Streptococcus infections; Streptococcus pneumoniae; Streptococcus pneumoniae - immunology; Tauroursodeoxycholic acid; Therapeutic applications; ER stress; macrophage; aging; pneumonia; inflammasome
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00393.2017

Pneumococcal infections are the eigth leading cause of death in the United States, and it is estimated that older patients (≥65 yr of age) account for the most serious cases. The goal of our current study is to understand the impact of biological aging on innate immune responses to Streptococcus pneumoniae, a causative agent of bacterial pneumonia. With the use of in vitro and in vivo aged murine models, our findings demonstrate that age-enhanced unfolded protein responses (UPRs) contribute to diminished inflammasome assembly and activation during S. pneumoniae infection. Pretreatment of aged mice with endoplasmic reticulum chaperone and the stress-reducing agent tauroursodeoxycholic acid (TUDCA) decreased mortality in aged hosts that was associated with increased NLRP3 inflammasome activation, improved pathogen clearance, and decreased pneumonitis during infection. Taken together, our data provide new evidence as to why older persons are more susceptible to S. pneumoniae and provide a possible therapeutic target to decrease morbidity and mortality in this population.